EHRA PRACTICAL GUIDE Europace (2013) 15, 625–651 doi:10.1093/europace/eut083 European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation Hein Heidbuchel 1*, Peter Verhamme 1, Marco Alings 2, Matthias Antz 3, Werner Hacke 4, Jonas Oldgren5, Peter Sinnaeve 1, A John Camm 6, and Paulus Kirchhof 7,8 Received November 2012; accepted after revision 18 March 2013 New oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular atrial fibrillation (AF) Both physicians and patients will have to learn how to use these drugs effectively and safely in clinical practice Many unresolved questions on how to optimally use these drugs in specific clinical situations remain The European Heart Rhythm Association set out to coordinate a unified way of informing physicians on the use of the different NOACs A writing group listed 15 topics of concrete clinical scenarios and formulated as practical answers as possible based on available evidence The 15 topics are: (1) Practical start-up and follow-up scheme for patients on NOACs; (2) How to measure the anticoagulant effect of NOACs; (3) Drug–drug interactions and pharmacokinetics of NOACs; (4) Switching between anticoagulant regimens; (5) Ensuring compliance of NOAC intake; (6) How to deal with dosing errors; (7) Patients with chronic kidney disease; (8) What to if there is a (suspected) overdose without bleeding, or a clotting test is indicating a risk of bleeding? (9) Management of bleeding complications; (10) Patients undergoing a planned surgical intervention or ablation; (11) Patients undergoing an urgent surgical intervention; (12) Patients with AF and coronary artery disease; (13) Cardioversion in a NOAC-treated patient; (14) Patients presenting with acute stroke while on NOACs; (15) NOACs vs VKAs in AF patients with a malignancy Since new information is becoming available at a rapid pace, an EHRA Web site with the latest updated information accompanies this text (www.NOACforAF.eu) Keywords Atrial fibrillation † Anticoagulation † Stroke † Bleeding † Pharmacology Introduction New oral anticoagulants (NOACs) have emerged as an alternative for vitamin K antagonists (VKAs) for thromboembolic prevention in patients with non-valvular atrial fibrillation (AF) This will have an impact on many practical considerations in the daily management of these patients Although very promising in many regards (predictable effect without need for monitoring, fewer food and drug interactions, shorter plasma half-life, and an improved efficacy/safety ratio), the proper use of NOACs will require new approaches in many daily aspects Whereas the 2010 ESC Guidelines (and the 2012 Update)1,2 mainly discuss the indications for anticoagulation in general (e.g based on the CHA2DS2-VASc score) and of NOAC in particular, they guide less on how to * Corresponding author Tel: +32-16-34 42 48; fax: +32-16-34 42 40, Email: Hein.Heidbuchel@uzleuven.be Advisors: Azhar Ahmad, M.D (Boehringer Ingelheim Pharma), Susanne Hess, M.D (Bayer Healthcare Pharmaceuticals), Felix Muănzel, Ph.D (Daiichi Sankyo Europe), Markus Schwertfeger, M.D (Daiichi Sankyo Europe), Martin van Eickels, M.D (Bayer Healthcare Pharmaceuticals), Jean-Philippe Verbist, M.D (Bristol Myers Squibb/Pfizer) Document reviewers: Coordinator: Antonio Raviele, Alliance to Fight Atrial Fibrillation (ALFA), Venice-Mestre, Italy Leandro Zimerman, M.D (Hospital de Clı´nicas de Porto Alegre, Brasil), Chern-En Chiang, Ph.D (Taipei Veterans General Hospital, Taiwan), Hans Diener, Ph.D (University of Essen, Germany), Giuseppe Di Pasquale, Ph.D (Ospedale Maggiore, Bologna, Italy), Stephan Hohnloser, Ph.D (Klinikum der J.-W.-Goethe-Universitat, Frankfurt, Germany), Jean-Yves Le Heuzey, Ph.D (Hopital Europeen Georges Pompidou, Paris, France), Jose` Lopez-Sendon, Ph.D (Hospital Universitario La Paz Madrid, Spain, Jonas Bjerring Olesen, Ph.D (Copenhagen University Hospital Gentofte, Denmark), Frans H Rutten, Ph.D (Julius Center UMC Utrecht, The Netherlands), Marco Valgimigli, Ph.D (University Hospital of Ferrara, Italy), Freek W.A Verheugt, Ph.D (Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands), Michael Brainin, Ph.D (Klinische Medizin Und Praeventionsmedizin, Danube University Krems, Austria), Kennedy Lees, Ph.D (University of Glasgow, UK) Published on behalf of the European Society of Cardiology All rights reserved & The Author 2013 For permissions please email: journals.permissions@oup.com Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 Department of Cardiovascular Medicine, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium; 2Department of Cardiology, Amphia Ziekenhuis, Breda, Netherlands; 3Department of Cardiology, Klinikum Oldenburg, Oldenburg, Germany; 4Department of Neurology, Ruprecht Karls Universitaăt, Heidelberg, Germany; 5Uppsala Clinical Research Center and Dept of Medical Sciences, Uppsala University, Uppsala, Sweden; 6Clinical Cardiology, St George’s University, London, UK; 7University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK; and 8Department of Cardiology and Angiology, University of Muănster, Germany 626 Practical start-up and follow-up scheme for patients on new oral anticoagulants 1.1 Start of therapy Before prescribing a NOAC to a patient with AF, it should have been decided that anticoagulation is merited and that the use of a novel agent is appropriate Thus, a risk/benefit, analysis relating to anticoagulation is in favour of the treatment, and the choice of anticoagulant has been made on the basis of approved indications as provided by regulatory authorities, professional societies and local formulary committees, and on the preference of the patient after discussion of the different options.1 The general indications for anticoagulation are fully explained in professional guidelines and the specific indications for NOACs are outlined in relevant SmPC and local agreements/regulations Table lists the NOACs approved or under evaluation for stroke prevention in AF patients It should be appreciated that in many countries not all NOACs share precisely the same indication and that local factors, especially with regard to the cost of therapy may influence their use Concerning the choice of a given NOAC, it is also important to consider co-medications taken by the patient, some of which may be contraindicated or pose unfavourable drug– drug interactions (see Section 4) Alternatively, some co-medications such as proton pump inhibitors (PPI) may be considered to reduce the risk for gastro-intestinal bleeding Users of VKAs have routinely been advised to carry information about their anticoagulant therapy to alert any (para)medical participant in their care It should be equally important that those treated with NOACs carry details of this therapy Each manufacturer provides proprietary information cards, but it is suggested that a uniform card should be completed and carried by each patient Figure shows a proposal for such a card, which can be downloaded in digital form at www.NOACforAF.eu It is critically important to educate the patient about the importance of daily intake of NOACs at each visit, and to convince them that a NOAC should not be discontinued because of the rapid decline of protective anticoagulation that will occur Similarly, Table New anticoagulant drugs, approved or under evaluation for prevention of systemic embolism or stroke in patients with non-valvular atrial fibrillation a No EMA approval yet Needs update after finalization of SmPC bid, twice daily; qd, once daily See further Tables and text for discussion on dose considerations Hatching, as (being) studied in Phase clinical trial; not yet approved by EMA Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 deal with NOAC in specific clinical situations Moreover, despite the different AF anticoagulation trials, there are still many under-explored aspects of NOAC that are relevant already today when these drugs are used by cardiologists, neurologists, geriatricians, and general practitioners Each of the new NOACs entering the market will be accompanied by tools for its proper use in many clinical situations (Summary of Product Characteristics or SmPC; patient card; information leaflets for patients and physicians), but there is a risk that multiple, and often slightly different, physician education tools could lead to more confusion than clarity Based on these premises, the European Heart Rhythm Association (EHRA) set out to coordinate a unified way of informing physicians on the use of NOACs This document thus supplements the AF guidelines as a practical guidance tool for safe, effective use of NOAC when prescribed A writing group listed 15 topics of concrete clinical scenarios, and formulated as practical answers as possible based on available knowledge The writing group was assisted by medical experts of the companies that bring NOACs to the market: they assured that the latest information on the different NOAC was evaluated, and provided feedback on the alignment of the text with the approved SmPC Nevertheless, the responsibility of this document resides entirely with the EHRA writing group, also because in some instances we opted to make recommendations beyond the information available in SmPC in order to provide practice advice to physicians in the field Since new information is becoming available at a rapid pace, an EHRA Web site with the latest updated information accompanies this text (www.NOACforAF.eu, which links to www.escardio.org/ COMMUNITIES/EHRA, under ‘Publications’) Any item that has been changed from the original printed version will be highlighted in the future Please note that not all drugs discussed in this document may already be European medicines agency (EMA) approved for the non-valvular AF indication, and/or not available in the different constituent EU countries at the time of publication of this document We hope that this collaborative effort has yielded the practical tool that EHRA envisioned The authors realize that there will be gaps, unaddressed questions, and many areas of uncertainty/debate Therefore, readers can address their suggestions for change or improvement on the web site This whole endeavour should be one for and by the medical community H Heidbuchel et al EHRA practical guide for use of the new oral anticoagulants 627 Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 Figure European Heart Rhythm Association proposal for a universal NOAC anticoagulation card A patient information card is crucial, both for the patient (instructions on correct intake; contact information in case of questions) as for health care workers (other care-takers are involved; renal function; follow-up schedule; concomitant medication ) We present a generic and universal card that could serve all patients under NOAC therapy 628 H Heidbuchel et al forgetting to take the medication or leaving it behind when travelling is dangerous This should be carefully explained to the patient who should be made aware of the importance of strict adherence to the prescribed NOAC regimen 1.2 How to organize follow-up? Initiator of anticoagulant treatment: - Sets indication for anticoagulation; - Makes choice of anticoagulant; - Decides on need of proton pump inhibitor; - Baseline hemoglobin, renal and liver function; - Provides education; - Hands out anticoagulation card; - Organises follow-up (when, by whom, what?); - Remains responsible coordinator for follow-up First FU: month Follow-up: GP; anticoagulant clinic; initiator of therapy; m? 3m - Checks: Compliance (patient should bring remaining oills); Thrombo-embolic events; Bleeding events; Other side effects; Co-medications and over-the-counter drugs; Need for blood sampling? 6m In case of problems: contacts initiator of treatment Else: Fills out anticoagulation card and sets date/place for next follow-up Figure Structured follow-up of patients on NOACs It is mandatory to ensure safe and effective drug intake The anticoagulation card, as proposed in Figure 1, is intended to document each planned visit, each relevant observation or examination, and any medication change, so that every person following up the patient is well-informed Moreover, written communication between the different (para)medical players is required to inform them about the follow-up plan and execution Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 The follow-up of AF patients who are taking anticoagulant therapy should be carefully specified and communicated among the different caretakers of the patient All anticoagulants have some drug – drug interactions and they may cause serious bleeding Therapy prescription with this new class of drugs requires vigilance, also because this is a fragile patient population and NOACs are drugs with potentially severe complications Patients should return on a regular basis for on-going review of their treatment, preferably every months This review may be undertaken by general practitioners with experience in this field and/or by appropriate secondary care physicians (Figure 2) Nurse-coordinated AF clinics may be very helpful in this regard.7,8 Regular review has to systematically document (1) therapy adherence (ideally with inspection of the prescribed medication in blister packs or bottles, in addition to appropriate questioning); (2) any event that might signal thromboembolism in either the cerebral, systemic or pulmonary circulations; (3) any adverse effects, but particularly (4) bleeding events (occult bleeding may be revealed by falling haemoglobin levels, see below); (5) co-medications, prescribed or over-the-counter; and (6) blood sampling for haemoglobin, renal (and hepatic) function Table lists the appropriate timing of these evaluations, taking the patient profile into consideration For example, renal function should be assessed more frequently in patients receiving dabigatran, or in potentially compromised patients such as the elderly, otherwise frail patients, or in those where an intercurring condition may affect renal function, since all NOACs require dose reductions depending on renal function (see Sections and 8; see Table of the ESC AF Guidelines Update2) Although the RE-LY protocol did not specify dose reduction in patients with chronic kidney disease and a CrCl of 30–50 ml/min (unless e.g 629 EHRA practical guide for use of the new oral anticoagulants Table Checklist during follow-up contacts of AF patients on anticoagulation Interval Comments Compliance Each visit Thrombo-embolism Each visit Bleeding Each visit † † † † † † † Each visit † Co-medications Each visit Blood sampling Yearly monthly monthly On indication † † † † † † TIA, transient ischaemic attack; PPI, proton pump inhibitor; CrCl, creatinine clearance (preferably measured by the Cockroft method) Table Interpretation of coagulation assays in patients treated with different NOACs a No EMA approval yet Needs update after finalization of SmPC Routine monitoring is not required Assays need cautious interpretation for clinical use in special circumstances, as discussed in the text PT, prothrombin time; aPTT, activated partial thromboplastin time; dTT, diluted thrombin time; INR, international normalized ratio; ULN, upper limit of normal HAS-BLED ≥3; see Section and Table 7), its higher renal clearance makes it more vulnerable to acute regression of kidney function Minor bleeding is a particular problem in patients treated with any anticoagulant It is best dealt with by standard methods to control bleeding, but should not lead readily to discontinuation or dose adjustment of therapy Minor bleeding is not necessarily predictive of major bleeding risk Most minor bleeding is temporary and is best classified as ‘nuisance’ in type Obviously when such bleeding occurs frequently the patient’s quality of life might be degraded and the specific therapy or dose of medication might Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 Other side effects Instruct patient to bring remaining medication: note and calculate average adherence Re-educate on importance of strict intake schedule Inform about compliance aids (special boxes; smartphone applications; ) Systemic circulation (TIA, stroke, peripheral) Pulmonary circulation ‘Nuisance’ bleeding: preventive measures possible? (PPI; haemorrhoidectomy; ) Motivate patient to diligently continue anticoagulation Bleeding with impact on quality-of-life or with risk: prevention possible? Need for revision of anticoagulation indication or dose? Carefully assess relation with NOAC: decide for continuation (and motivate), temporary cessation (with bridging), or change of anticoagulant drug Prescription drugs; over-the-counter drugs (see Section 4) Careful interval history: also temporary use can be risk! Haemoglobin, renal and liver function Renal function if CrCl 30–60 ml/min, or if on dabigatran and 75 years or fragile If CrCl 15–30 ml/min If intercurring condition that may impact renal or hepatic function 630 How to measure the anticoagulant effect of new oral anticoagulants? 2.1 Direct thrombin inhibitor (dabigatran) For dabigatran, the aPTT may provide a qualitative assessment of dabigatran level and activity The relation between dabigatran and the aPTT is curvilinear (Figure 3).12 Nevertheless, the sensitivity of the different aPTT reagents varies greatly In patients receiving chronic therapy with dabigatran 150 mg twice daily (bid), the median peak aPTT was approximately two-fold that of control Twelve hours after the last dose, the median aPTT was 1.5-fold 2.2 Factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) The different Factor Xa-inhibitors affect the PT and the aPTT to a varying extent The aPTT cannot be used for any meaningful evaluation of FXa inhibitory effect because of the weak 3.6 3.2 2.8 2.4 2.0 Multiple dose y = 0.86 + 0.06873×1/2 r2 = 0.8514 1.6 1.2 0.9 200 400 600 800 1000 Dabigatran plasma concentration [ng/mL] Figure Curvilinear relation between aPTT and dabigatran plasma levels From van Ryn et al.,12 with permission Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 New oral anticoagulants not require routine monitoring of coagulation: neither the dose nor the dosing intervals should be altered in response to changes in laboratory coagulation parameters for the current registered indications However, the quantitative assessment of the drug exposure and the anticoagulant effect may be needed in emergency situations, such as a serious bleeding and thrombotic events, need for urgent surgery, or in special clinical situations such as patients who present with renal or hepatic insufficiency, in case of potential drug–drug interactions or of suspected overdosing When interpreting a coagulation assay in a patient treated with a NOAC, in contrast to VKA coagulation monitoring, it is paramount to know exactly when the NOAC was administered relative to the time of blood sampling The maximum effect of the NOAC on the clotting test will occur at its maximal plasma concentration, which is approximately h after intake for each of these drugs A coagulation assay obtained on a blood sample taken h after the ingestion of the NOAC (at peak level) will demonstrate a much larger impact on the coagulation test than when performed at trough concentration, i.e 12 or 24 h after ingestion of the same dose Even a sample taken h after drug intake will yield different results Moreover, depending on the clinical profile of the patient, an estimation of the elimination half-life should be done: especially with dabigatran, this is dependent on the kidney function (see Section 8) The time delay between intake and blood sampling should therefore be carefully recorded when biological monitoring is performed The activated partial thromboplastin time (aPTT) may provide a qualitative assessment of the presence of dabigatran and the prothrombin time (PT) for rivaroxaban (and likely other factor Xa inhibitors), but these respective tests are not sensitive for the quantitative assessment of the NOAC Quantitative tests for direct thrombin inhibitors (DTIs) and FXa inhibitors exist, but they may not (yet) be routinely available in most hospitals Point of care tests should not be used to assess the international normalized ratio (INR) in patients on NOACs.11 An overview of the interpretation of all the coagulation tests for different NOACs can be found in Table and will be discussed in more detail below that of control, with less than 10% of patients exhibiting two-fold increases Therefore, if the aPTT level at trough (i.e 12–24 h after ingestion) still exceeds two times the upper limit of normal, this may be associated with a higher risk of bleeding, and may warrant caution especially in patients with bleeding risk factors.12 Dabigatran has little effect on the PT and INR at clinically relevant plasma concentrations, resulting in a very flat response curve The INR is therefore unsuitable for the quantitative assessment of the anticoagulant activity of dabigatran.12 The ecarin clotting time (ECT) assay provides a direct measure of the activity of DTIs, but may not be readily available When dabigatran is used, with twice daily dosing, ≥3 times elevated ECT at trough is associated with a higher risk of bleeding.13 The results of a diluted thrombin time (dTT) test can more accurately predict the coagulation state However, thrombin time results depend on the coagulometer and the thrombin lot used A dTT has been developed, with appropriate calibrators for interpretation in the context of dabigatran use (Hemoclotw) The dTT displays a direct linear relationship with dabigatran concentration It is prolonged already at low concentrations of dabigatran It is suitable for the quantitative assessment of dabigatran concentrations A normal dTT measurement indicates no clinically relevant anticoagulant effect of dabigatran When dabigatran is used with twice daily dosing, a dTT measured at trough (≥12 h after the previous dose) with the Hemoclotw of 200 ng/mL dabigatran plasma concentration (i.e dTT approximately 65 s), is associated with an increased risk of bleeding.13 It is important to note that there are no data on a cut-off dTT below which elective or urgent surgery is ‘safe’, and therefore its use in this respect cannot be recommended at this time (see also Sections 11 and 12) aPTT [ratio] require review, but this should be undertaken very carefully to avoid depriving the patient of the very valuable thromboprophylactic effect of the therapy H Heidbuchel et al 631 EHRA practical guide for use of the new oral anticoagulants Time (s) 100 50 Triniclot PT excel S (STA) r2 = 0.99 Neoplastine R (STA) r2 = 0.99 Recombiplastin (ACLTOP) r2 = 1.00 Neoplastine Cl+ (STA) r2 = 0.98 Triniclot PT HTF (STA) r2 0.99 Triniclot PT excel (STA) r2 = 0.99 Innovin (BCS) r2 = 0.99 5th-95th percentile interval in simulated AF population at Cmax 5th-95th percentile interval in simulated AF population at Ctrough 150 500 Initial [rivaroxaban] (ng/mL) 1000 Figure Relation between PT and FXa inhibitor (rivaroxaban) plasma levels But the sensitivity is dependent on the reagent used The figure shows data for rivaroxaban The slopes will vary for other FXa inhibitors and reagents Moreover, as in Figure 3, there is a high variation of measured values at different concentrations It is clear that only qualitative information can be gained, without precise measurement of the anticoagulant effect From Douxils et al.15 with permission prolongation, variability of assays, and paradoxical response at low concentrations.14 Factor Xa-inhibitors demonstrate a concentration-dependent prolongation of the PT Nevertheless the effect on the PT depends both on the assay and on the FXa inhibitor For rivaroxaban, the PT may provide some quantitative information, even though the sensitivity of the different PT reagents varies greatly (Figure 4) If Neoplastin Plus or Neoplastin is used as thromboplastin reagent, the PT is influenced in a dose-dependent manner with a close correlation to plasma concentrations.16 Neoplastin Plus is also more sensitive than Neoplastin.14 Assay-specific calibrators and calibration curves can be made (Figure 4) There are currently no such data available for edoxaban and apixaban Importantly, the INR (and certainly a point-of-care determined INR) is completely unreliable for the evaluation of FXa inhibitory activity Anti-FXa ‘chromogenic assays’ have been developed to assess plasma concentrations of the FXa-inhibitors using validated calibrators and are commercially available Low and high plasma levels can be measured with acceptable inter-laboratory precision However, there are currently no data that associate a coagulation parameter or a drug level at trough or at peak with bleeding risk or risk for thrombo-embolism 2.3 Impact of new oral anticoagulants on coagulation system assessment The NOACs interfere with routine coagulation tests, but also with thrombophilia tests or the measurement of coagulation factors Abnormal coagulation tests should be interpreted with caution if the time window between blood sampling and NOAC intake is unknown Therefore, a time window of at least 24 h is recommended between the last intake of a NOAC and blood sampling to assess coagulation parameters and this time window may be even longer for lupus anticoagulant measurements (≥48 h) Drug –drug interactions and pharmacokinetics of new oral anticoagulants Treatment with VKAs requires careful consideration of multifold food and drug interactions Despite high expectations of less interactions with the NOAC drugs, physicians will have to consider pharmacokinetic effects of accompanying drugs and of comorbidities when prescribing NOACs This section wants to provide a simple guide to deal with such situations However, every patient may require more specific consideration, especially when a combination of interfering factors is present Moreover, the knowledge base on interactions (with effect on plasma levels and/or on clinical effects of NOAC drugs) is expanding, so that new information may modify existing recommendations Check the web site accompanying this text for the most up-to-date information (www NOACforAF.eu) The uptake, metabolization and elimination of the different NOACs are graphically depicted in Figure and summarized in Table We believe that anyone involved in the treatment of patients with NOACs should have this information at hand An important interaction mechanism for all NOACs except rivaroxaban consists of significant re-secretion over a P-glycoprotein (P-gp) transporter after absorption in the gut Moreover, the P-gp transporter may also be involved in renal clearance (also for Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 632 H Heidbuchel et al Table Absorption and metabolism of the different NOACs Dabigatran Apixaban Edoxabana Rivaroxaban Bio-availability –7% 50% 62%17 66% without food Almost 100% with food Prodrug Clearance non-renal/renal of absorbed dose (if normal renal function; see also Section 8) Yes 20%/80% No 73%/27%18 No 50%/50%9 No 65%/35% Liver metabolism: CYP3A4 involved No Yes (elimination; minor CYP3A4 contribution)19 Minimal (,4% of elimination) Yes (elimination) Absorption with food Intake with food recommended? No effect No No effect No 6– 22% more20 No official recommendation yet +39% more21 Mandatory Absorption with H2B/PPI 212– 30%22 – 24 No effect No effect No effect21,25 Asian ethnicity GI tolerability +25% Dyspepsia 5– 10% 12–17 h23 Elimination half-life 24 a No EMA approval yet Needs update after finalization of SmPC H2B, H2-blocker; PPI, proton-pump inhibitor; GI, gastro-intestinal 20 No effect No problem No effect No problem No effect No problem 12 h 9– 11 h9 –9 h (young) 11– 13 h (elderly) Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 Figure Absorption and metabolism of the different new anticoagulant drugs There are interaction possibilities at the level of absorption or first transformation, and at the level of metabilisation and excretion The brackets around (Cyp3A4) in the apixaban graph indicate a minor contribution of this pathway to hepatic clearance, the majority of the drug being excreted as unchanged parent See also Table for the size of the interactions based on these schemes 633 EHRA practical guide for use of the new oral anticoagulants 3.1 Food intake and antacids Intake with food does not affect dabigatran absorption, which therefore can be taken irrespective of meals Since food intake has an impact on the absorption and bioavailability of rivaroxaban (area under the curve plasma concentrations increase by 39%), the official recommendation is to take rivaroxaban with food (resulting in almost complete absorption and a very high bioavailability of almost 100%) There is no relevant food interaction for edoxaban,20 nor for apixaban which may be taken with or without food Absorption of dabigatran in the gastro-intestinal tract is dependent on an acid milieu, which is provided by the formulation of the drug Concomitant use of PPIs and H2-blockers leads to a small reduced bioavailability but without effect on clinical efficacy.22,23 Therefore, antacid intake does not constitute a contraindication for dabigatran use 3.2 Rate and rhythm control drugs Rate-controlling and anti-arrhythmic drugs interact with P-gp, hence warranting caution for concomitant use of NOACs The P-gp effects of verapamil are dependent on the formulation: when an immediate release preparation is taken within h of dabigatran intake (mainly if before), plasma levels of dabigatran may increase up to 180% Separating both drugs’ intake ≥2 h removes the interaction (but is hard to guarantee safely in clinical practice) With a slow-release verapamil preparation, there may be a 60% increase in dabigatran dose Observational data from the RE-LY trial showed an average 23% increase in dabigatran levels in patients taking (all sorts) of verapamil.24 A similar interaction has been noted for edoxaban.5 Therefore, for both drugs it is advised to reduce the NOAC dose when used in combination with verapamil (‘orange’) Diltiazem has a lower inhibitory potency of P-gp, resulting in non-relevant interactions, although there is a 40% increase in plasma concentrations of apixaban (‘yellow’; Table 5).24 There is a strong effect of dronedarone on dabigatran plasma levels, which constitutes a contraindication for concomitant use No data are available yet for FXa-inhibitors, but a similar caution may be warranted Although amiodarone increases the dabigatran plasma levels slightly, there is no need for dose reduction of dabigatran when only amiodarone is interacting, although other factors should be evaluated (‘yellow’) 3.3 Other drugs Table lists the potential interaction mechanisms for other drugs, and their clinical relevance Since some drugs are both inhibitors of CYP3A4 and of P-gp, they may have an effect on plasma levels although either the P-gp or CYP3A4 effect by itself is minimal In general, although the NOACs are substrates of CYP enzymes or P-gp/BCRP (breast cancer resistance protein), they not inhibit those Therefore, they can be co-administered with substrates of CYP3A4 (e.g midazolam), P-gp (e.g digoxin), or both (e.g atorvastatin) without concern of changing the plasma levels of these drugs 3.4 Pharmacodynamic interactions Apart from the pharmacokinetic interactions, it is clear that association of NOACs with other anticoagulants, platelet inhibitors (aspirin, clopidogrel, ticlodipine, prasugrel, ticagrelor, and others), and non-steroidal anti-inflammatory drugs increases the bleeding risk There are data indicating that the bleeding risk in association with antiplatelet agents increases by at least 60% (similar as in association with VKAs).36 – 38 Therefore, such associations should be carefully balanced against the potential benefit in each clinical situation Association of NOACs with dual antiplatelet drugs requires active measures to reduce time on triple therapy (see Section 13) Switching between anticoagulant regimens It is important to safeguard the continuation of anticoagulant therapy while minimizing the risk for bleeding when switching between different anticoagulant therapies This requires insights into the pharmacokinetics and pharmacodynamics of different anticoagulation regimens, interpreted in the context of the individual patient Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 rivaroxaban)26: competitive inhibition of this pathway therefore will result in increased plasma levels Many drugs used in AF patients are P-gp substrates (e.g verapamil, dronedarone, amiodarone, quinidine) CYP3A4 type cytochrome P450-dependent elimination is involved in rivaroxaban and apixaban hepatic clearance.27 Strong CYP3A4 inhibition or induction may affect rivaroxaban plasma concentrations and effect, and should be evaluated in context (see below) Most of the hepatic clearance of apixaban is as unchanged molecule, with only a minority being metabolized (in part via CYP3A4), which makes CYP3A4 interactions of less importance for this drug.19 Nevertheless, its SmPC indicates that apixaban should be used with caution if co-administered with strong inducers of both CYP3A4 and P-gp, and is contra-indicated in combination with strong inhibitors of both CYP3A4 and P-gp It seems that for edoxaban, CYP3A4 is only weakly involved, but caution is still warranted until more definitive interaction data are available The bio-availability of dabigatran is markedly lower than that of the other drugs (Table 4).22 This means that slight fluctuations in absorption or elimination may have a greater impact on the plasma levels than with other drugs There is good rationale for reducing the dose of NOACs in patients with a high bleeding risk and/or when a higher plasma level of the drug can be anticipated.1,4,28 We have chosen an approach with three levels of alert for drug–drug interactions or other clinical factors that may affect NOAC plasma levels or effects (Table 5): (1) ‘red’ interactions, precluding the use of a given NOAC in combination (i.e ‘contraindication’ or ‘discouragement’ for use); (2) ‘orange’ interactions, with the recommendation to adapt the NOAC dose, since they result in changes of the plasma levels or effect of NOACs that could potentially have a clinical impact; and (3) ‘yellow’ interactions, with the recommendation to keep the original dose, unless two or more concomitant ‘yellow’ interactions are present Two or more ‘yellow’ interactions need expert evaluation, and may lead to the decision of not prescribing the drug (‘red’) or of adapting its dose (‘orange’) Unfortunately, for many potential interactions with drugs that are often used in AF patients no detailed information is available yet These have been shaded in the table It is prudent to abstain from using NOACs in such circumstances until more information is available 634 H Heidbuchel et al Table Effect on NOAC plasma levels (‘area under the curve, AUC’) from drug –drug interactions and clinical factors, and recommendations towards NOAC dosing Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 Red, contraindicated/not recommended Orange, reduce dose (from 150 mg bid to 110 mg bid for dabigatran; from 20 mg to 15 mg qd for rivaroxaban; from mg bid to 2.5 mg bid for apixaban) Yellow, consider dose reduction if another ‘yellow’ factor is present Hatching, no data available; recommendation based on pharmacokinetic considerations a No EMA approval yet Needs update after finalization of SmPC b Prespecified dose reduction has been tested in Phase clinical trial (to be published) BCRP, breast cancer resistance protein; NSAID, non-steroidal anti-inflammatory drugs; H2B, H2-blockers; PPI, proton pump inhibitors; P-gp, P-glycoprotein; GI, gastro-intestinal 4.1 Vitamin K antagonist to new oral anticoagulant The NOAC can immediately be initiated once the INR is lower than 2.0 If the INR is 2.0 – 2.5, NOACs can be started immediately or (better) the next day For INR 2.5, the actual INR value and the half-life of the VKA need to be taken into account to estimate the time when the INR value will likely drop to below this threshold value: acenocoumarol t12 8–14 h, warfarin t12 36 –42 h, phenprocoumon t12 days (120 –200 h) At that time, a new INR measurement can be scheduled 637 EHRA practical guide for use of the new oral anticoagulants Table Estimated drug half-lives and effect on area under the curve NOAC plasma concentrations in different stages of chronic kidney disease compared to healthy controls a No EMA approval yet Needs update after finalisation of SmPC CKD, chronic kidney disease; CrCl, creatinine clearance Hatching, no available data yet Orange, reduce dose (from 150 mg BID to 100 mg BID for dabigratran) Yellow, consider dose reduction if another ’yellow’ factor is present (from 20 mg to 15 mg QD for rivaroxaban; from mg BID to 2.5 mg BID for apixaban) Hatching, no data available yet a No EMA approval yet Needs update after finalisation of SmPC b No EMA indication FDA recommendation based on pharmacokinetics Carefully weigh risks and benefits of this approach Note that 75 mg capsules are not available on the European market for AF indication CKD, chronic kidney disease; CrCl, creatinine clearance; bid, twice daily; qd, once daily; SmPC, summary of product characteristics and should be considered in patients with CrCl ,50 ml/min along the guidance of Tables and (4) In the absence of clinical data or experience, NOAC therapy should be avoided in AF patients on haemodialysis Vitamin K antagonists may be a more suitable alternative for now Even the benefit of VKAs in haemodialysis patients is not unequivocally proven, however Vitamin K deficiency secondary to malnutrition, frequent antibiotic use, and abnormal cholesterol metabolism may lead to fluctuations in responsiveness to VKAs Therefore, a careful individualised risk/benefit for anticoagulation is warranted Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 Table NOACs in renal dysfunction: Approved European labels and dosing in chronic kidney disease 638 H Heidbuchel et al (5) In patients on NOACs, renal function needs to be monitored carefully, at least yearly, to detect changes in renal function and adapt the dose accordingly If renal function is impaired (≤60 ml/min), monthly checks are required Renal function monitoring is especially relevant for dabigatran, which is predominantly cleared renally: in elderly patients (.75 years) or otherwise frail patients on dabigatran, renal function should be evaluated at least once every months (see also Table and Figure 2) Acute illness often transiently affects renal function (infections, acute heart failure, ), and therefore should trigger re-evaluation (6) Renal function can deteriorate within a few months, and the nature of the kidney disease as well as concomitant conditions that could change the time course of CKD should be considered when deciding on a monitoring scheme What to if there is a (suspected) overdose without bleeding, or a clotting test is indicating a risk of bleeding? Doses of NOACs beyond those recommended expose the patient to an increased risk of bleeding This may occur when the patient has (intentionally) taken a too high dose or when intercurring events are suspected (like renal insufficiency, especially with dabigatran; administration of drugs that may lead to drug– drug interactions; or other factors: see Section 4) that may have increased plasma concentration of the NOAC beyond therapeutic levels In terms of management, it is important to distinguish between an overdose with and without bleeding complications In case of bleeding complications, see Section 10 Rare cases of overdose have been reported without bleeding complications or other adverse reactions in the clinical trials Interestingly, as result of limited absorption, a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of ≥50 mg rivaroxaban.51 There are no data in this respect concerning the other FXa inhibitors In the case of recent acute ingestion of an overdose, the use of activated charcoal to reduce absorption may be considered for any NOAC (with a standard dosing scheme for adults of 30 –50 g) In case of an overdose suspicion, coagulation tests can help to determine its degree and possible bleeding risk (see Section for the interpretation of coagulation tests) There are currently no specific antidotes for the NOACs, although development for those is ongoing However, given the relatively short plasma half life of the NOAC drugs, in the absence of bleeding a ‘wait-and-see’ management can be advocated in most cases If a more aggressive normalization of plasma levels is deemed necessary, or rapid normalization is not expected (e.g major renal insufficiency) the steps outlined in Section 10 can be taken At this point in time the different NOACs share the fact that specific antidotes and rapid (routine) quantitative measurements of their anticoagulant are missing (see also Section 3), and strategies for reversal of the anticoagulant effects are limited Reversal of the effects of VKAs through the administration of vitamin K has a slow onset (i.e at least 24 h), but administration of fresh frozen plasma or coagulation factors more rapidly restores coagulation In case of NOACs, however, the plasma abundance of the drug may block newly administered coagulation factors as well On the other hand, restoration of coagulation does not necessarily equal good clinical outcome, and studies have shown that the bleeding profile of NOACs, in particular that of intracranial and other lifethreatening bleeding, is more favourable than that of warfarin Nevertheless, as more patients will start using one of the NOACs, the number of bleeding-related events is expected to increase Currently, recommendations on bleeding management are not so much based on clinical experience, but rather reflect experts’ opinions or laboratory endpoints 9.1 Non life-threatening bleeding In addition to standard supportive measurements (such as mechanical compression, surgical haemostasis, fluid replacement, and other haemodynamic support), in view of the relatively short elimination half lives, time is the most important antidote of the NOACs (see Table and Figure for a flowchart) After cessation of treatment, restoration of haemostasis is to be expected within 12 –24 h after the last taken dose, given plasma half-life of around 12 h for most NOACs.52 This underscores the importance to inquire about the used dosing regimen, the exact time of last intake, factors influencing plasma concentrations (like P-gp therapy, chronic kidney disease, and others, see also Table 5), and other factors influencing haemostasis (like concomitant use of anti-platelet drugs) Blood volume repletion and restoration of normal platelet count (in case of thrombocytopenia ≤60 × 109/L or thrombopathy) should be considered The time frame of drug elimination strongly depends on kidney function in patients taking dabigatran (see also Tables and 6) In case of bleeding in a patient using dabigatran, adequate diuresis must be maintained Although dabigatran can be dialysed, it should be noted that there is only limited clinical experience in using dialysis in this setting.12,53,54 Moreover, the risks of bleeding at puncture sites for dialysis needs to be balanced vs the risk of waiting In an open-label study in which a single 50 mg dose of dabigatran was administered to six patients with end-stage chronic kidney disease on maintenance haemodialysis, the mean fraction of drug removed by dialysis was 62% at h and 68% at h.48 Whether enhanced removal of dabigatran from plasma is possible via haemoperfusion over a charcoal filter is under evaluation.12 At this moment, the latter cannot be recommended in patients In contrast to dabigatran, dialysis has not been shown to be an option in patients treated with any of the FXa inhibitors since due to the high plasma binding of most FXa inhibitors, dialysis is not expected to significantly reduce their plasma levels Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 (i) Monitor every year for CKD stage I –II (CrCl ≥60 ml/min) (ii) Monitor every months for CKD stage III (CrCl 30 –60 ml/ min) (iii) Monitor every months for CKD stage IV (CrCl ≤30 ml/min) Management of bleeding complications 639 EHRA practical guide for use of the new oral anticoagulants Table Possible measures to take in case of bleeding Direct thrombin inhibitors (dabigatran) FXa inhibitors (apixaban, edoxaban, rivaroxaban) Inquire last intake + dosing regimen Estimate normalization of haemostasis: Normal renal function: 12–24 h CrCl 50–80 ml/min: 24–36 h CrCl 30–50 ml/min: 36–48 h CrCl ,30 ml/min: ≥48 h Inquire last intake + dosing regimen Normalization of haemostasis: 12–24 h Non life-threatening bleeding Maintain diuresis Local haemostatic measures Fluid replacement (colloids if needed) RBC substitution if necessary Platelet substitution (in case of thrombocytopenia ≤60 × 109/L or thrombopathy) Fresh frozen plasma as plasma expander (not as reversal agent) All of the above Prothrombin complex concentrate (PCC) 25 U/kg (may be repeated once or twice) (but no clinical evidence) Activated PCC 50 IE/kg; max 200 IE/kg/day): no strong data about additional benefit over PCC Can be considered before PCC if available Activated factor VII (rFVIIa; 90 mg/kg) no data about additional benefit + expensive (only animal evidence) RBC, red blood cells; CrCl, creatinine clearance; PCC, prothrombin complex concentrate 9.2 Life-threatening bleeding In mice, expansion of dabigatran-induced haematoma was prevented by administration of concentrates of coagulation factors II (VII), IX, and X (prothrombin complex concentrate, PCC, also called PPSB; some brand names are Cofactw, Confidexw, Octaplexw, and Beriplexw) in one study,55 but not in another one.56 In rabbits, Beriplexw inhibited dabigatran-induced bleeding in a rapid, dose-dependent manner.57,58 The effect of an overdose of rivaroxaban could be reversed in a rabbit model by recombinant activated factor VII (rFVIIa) and PCC as assessed by laboratory anticoagulation parameters (aPTT and thrombelastographic clotting time), but did not reverse rivaroxaban induced-bleeding.59 In healthy volunteers, administration of 50 U/kg of PCC completely reversed rivaroxaban-induced prolongation of the PT, but had no effect on dabigatran-induced prolongation of coagulation tests, in particular of thrombin time and ECTs.60 Bleeding time was not evaluated in this study Finally, in vitro testing using blood samples from volunteers taking rivaroxaban, dabigatran, or apixaban, showed that activated prothrombin complex concentrates (aPCC, i.e similar to PCC but with activated Factor VIIa; also called FEIBA; brand name Feibaw) corrected more coagulation parameters than PCC alone.61,62 Based on these (scarce) experimental data and given that the efficacy in patients who are actively bleeding has not been firmly established (i.e that they reduce blood loss and improve outcome),63 the administration of PCC or aPCC can be considered in a patient with life-threatening bleeding if immediate haemostatic support is required Awaiting more data on the clinical effectiveness of these strategies, the choice may depend on their availability and the experience of the treatment centre Based on studies with PCCs in preclinical models and in healthy volunteers, administration could start at a dose of 25 U/kg and can be repeated if clinically indicated Future studies might provide more information on dosing, and whether dosing should be adapted to the NOAC used Activated prothrombin complex concentrates (Feibaw, 50 IE/kg, with a maximum of 200 IE/kg/day), could be considered if it is readily available in the hospital The place of recombinant activated factor VIIa (NovoSevenw, 90 mg/kg) needs further evaluation.53 The use of other pro-coagulants such as antifibrinolytics (e.g tranexamic acid or aminocaproic acid) or desmopressin (especially in special situations with associated coagulopathy or thrombopathy) can be considered, though there are almost no clinical data of their effectiveness in NOAC-associated bleeding, and their use does not substitute the above mentioned measures Fresh frozen plasma will not be of help to reverse anticoagulation, but may be indicated to expand plasma volume in patients who require Downloaded from http://europace.oxfordjournals.org/ by guest on September 18, 2014 Life-threatening bleeding Tranexamic acid can be considered as adjuvans Desmopressin can be considered in special cases (coagulopathy or thrombopathy) Consider dialysis (preliminary evidence: -65% after h)48 Charcoal haemoperfusion not recommended (no data) All of the above Prothrombin complex concentrate (PCC) 25 U/kg (may be repeated once or twice) (but no clinical evidence) Activated PCC 50 IE/kg; max 200 IE/kg/day): no strong data about additional benefit over PCC Can be considered before PCC if available Activated factor VII (rFVIIa; 90 mg/kg) no data about additional benefit + expensive (only animal evidence) Local haemostatic measures Fluid replacement (colloids if needed) RBC substitution if necessary Platelet substitution (in case of thrombocytopenia ≤60 × 109/L or thrombopathy) Fresh frozen plasma as plasma expander (not as reversal agent) Tranexamic acid can be considered as adjuvans Desmopressin can be considered in special cases (coagulopathy or thrombopathy) 640 H Heidbuchel et al massive transfusion In the absence of a vitamin K deficiency or a treatment with VKAs, vitamin K administration has no role in the management of a bleeding under NOACs Similarly, protamine reverses the anticoagulant effects of heparin, but has no role in case of NOAC-associated bleeding We recommend consultation among cardiologists, haemostatis experts, and emergency physicians to develop a hospital-wide policy concerning bleeding management Such policy should be communicated well, and be easily accessible (e.g on an Intranet site or in pocket-sized leaflets) 10 Patients undergoing a planned surgical intervention or ablation Surgical interventions or invasive procedures that carry a bleeding risk require the temporary discontinuation of the NOAC Trials have shown that about one quarter of patients that are in need for anticoagulant therapy require temporary cessation within years.64 Both patient characteristics (kidney function, age, history of bleeding complications, concomitant medication) and surgical factors should be taken into account on when to discontinue and restart the drug, as indicated in Table Bridging was proposed in AF patients with higher thrombo-embolic risk treated with VKAs,1 but is not necessary in NOAC-treated patients since the predictable waning of the anticoagulation effect allows properly timed short-term cessation and reinitiation of NOAC therapy before and after surgery.64 Also other societies have formulated advice on temporary cessation of NOAC therapy.65 Again, we recommend the development of an institutional guideline and a hospital-wide policy concerning peri-operative Bleeding while using a NOAC Moderate severe bleeding Mild bleeding + • Delay or discontinue next dose • Reconsoder concomitant medication Life-threatening bleeding + Supportive measures: • Mechanical compression • Surgical hemostasis • Fluid replacement (colloids if needed) • RBC substitution if needed • Fresh frozen plasma (as plasma expander) • Platelet substitution (if platelet count